The most common cause of late Allograft failure, excluding death with a functioning graft in the case of kidney transplantation, is a clinicopathologic entity termed chronic rejection. Chronic rejection is common to all solid organ transplants, including kidney, heart, lung, pancreas and to a lesser extent, liver. Despite extensive research, the precise mechanisms responsible for the characteristic pathological and functional changes seen in chronic rejection remain unclear. The overall hypothesis of this Program Project is that the alloimmune response, and especially CD4+ T cell recognition of donor MHC peptides presented by self antigen-presenting cells (indirect allorecognition), is a central and key event that is responsible for the initiation and progression of chronic rejection. In addition, based on studies in small animals, alloantigen-independent mechanisms contribute to this process by promoting immune recognition and injury to the graft. Therefore, our goal is to study the contribution and mechanisms of the alloimmune response, along with interactions with key alloantigen-independent factors in the pathogenesis of chronic rejection in humans. In Project 1, Dr. Madsen and co-investigators will focus on studying the immunopathogenesis of chronic rejection using clinically relevant large animal (miniature swine) models of heart and lung transplantation. These models are unique in that they are the only large animal models with defined MHC systems and reproducible chronic rejection pathology. A major focus of Project 1 is to study immune responses to CMV and autoantigens in humans with chronic allograft rejection, as an extension of the studies in the miniature swine. In Project 2, Dr. Briscoe and colleagues plan to study the mechanisms of the interactions between donor endothelial cells and recipient antigen-presenting cells and T cells in promoting indirect alloimmune responses and chronic rejection. In Project 3, Dr. Sayegh's group will investigate the immunopathogenesis of chronic rejection with emphasis on the indirect alloimmune T cell and antibody response, and interactions with alloantigen-independent mechanisms in human renal transplant recipients. In the Scientific Core, Dr. Hancock will provide the infrastructure and technology to perform morphology, immunopathology and molecular analyses of tissue and peripheral blood mononuclear cells provided by the 3 Projects. Dr. Sayegh, along with Dr. Patricia Hibberd, Director of the Clinical Research Core Programs Office at Children's Hospital, will lead the Administrative and Data Management Core which will coordinate all administrative, statistical and data management issues of the Program Project. It is the collective results from our human studies in transplant recipients, our in vitro mechanistic experiments, and our large animal model that will provide a better understanding of the pathogenesis of chronic rejection. Our studies will yield clinically relevant information that will result in development of better assays to monitor and predict patients at risk for development of chronic rejection, as well as development of new therapeutic strategies to prevent this process.